SSRI augmentation of antipsychotic alters expression of GABAA receptor and related genes in PMC of schizophrenia patients

Abstract

Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)β3, 5-HT2A, and 5-HT7 receptors, PKCβ2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)β3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCβ2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCβ2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.

Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex

“…The alterations in PKC protein levels observed in rat brain are in line with the findings that PMC PKC mRNA levels were reduced in schizophrenia patients after addition of FLU, with statistically significant reduction observable at week 3 of treatment. This was of particular interest, since PKC is involved in cognition and PFC function (Arnsten 2009) and in patients, was associated negative symptom score at end of treatment (Silver et al 2010). For the GABAA receptor, chronic HALO-FLU in rats was associated with decrease in GABA-Aβ2/3 protein levels and apparent translocation from membrane to cytosol, consistent with downregulation.…”

“…For the GABAA receptor, chronic HALO-FLU in rats was associated with decrease in GABA-Aβ2/3 protein levels and apparent translocation from membrane to cytosol, consistent with downregulation. In patients, PMC mRNA coding for GABA-Aβ2/3 increased after 6 weeks of fluvoxamine augmentation treatment (Silver et al 2010). Closer examination of similarities and differences in clinical and preclinical findings may provide clues to guide further investigation.…”

“…In our study, PKC phosphorylation was not altered by HALO-FLU, so this mechanism cannot explain the effect of this treatment on muscimol-induced LORR, and involvement of other receptors, such as serotonin and dopamine, is suggested. Relevant to this may be the findings that schizophrenia patients showed significant increase in mRNA encoding for 5HT2A and 5HT7 receptors after SSRI was added to antipsychotic treatment (Silver et al 2010).…”

“…In a recent clinical study, we (Silver et al 2010) showed changes in GABA-Aβ2/3 mRNA and related systems, including PKC, in peripheral mononuclear cells (PMC) of schizophrenia patients following fluvoxamine augmentation. The patients were selected for the study as they had persistent negative symptoms despite adequate treatment with typical and atypical antipsychotics.…”

“…The clinical response of negative symptoms to SSRI augmentation of antipsychotic treatment is delayed (Silver et al 2003a, b), as are changes in PMC markers (Silver et al 2010), so it was of interest to examine the effects of chronic treatment with the SSRI-antipsychotic combination in the rat brain.…”